1. Field of the Invention
The present invention relates to a method of treating or preventing osteoporosis comprising administering to a patient in need thereof an effective amount of pharmaceutical composition comprising N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine, 4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine, or salts thereof, and alendronic acid or a salt thereof.
2. Description of the Related Art
Bone is a supporting material for the body's framework and serves to conserve the necessary bone mass and structure. Bone also functions as a reservoir of calcium (Ca2+) or the like, and plays an important role in maintaining the calcium level in the blood. The bone is in a dynamic steady state, ‘bone remodeling’ which maintains a delicate balance by continuously performing both bone resorption and bone formation. Bone remodeling is a complex process involving bone formation by osteoblasts and bone resorption and degradation by osteoclasts, and maintains a physiological and metabolic balance. However, the balance between bone resorption and bone formation is disrupted by various factors and diseases, leading to osteoporosis.
Osteoporosis is a bone disease, which results from a disturbance in the balance between bone resorption and bone formation, caused by having a higher degree of bone resorption relative to that of bone formation. This disease frequently occurs in middle-aged or elderly women. Osteoporosis reduces calcification of bone tissues, and decreases the level of the compact substances in the bone, which broadens the marrow cavity, and causes reduction in bone density or bone mass, resulting in decrease in bone strength. Consequently, as osteoporosis progresses, bone becomes brittle, and bone fracture may easily occur even with a small impact.
Bone fracture is associated with an increased mortality rate of patients with osteoporosis, and also causes serious problems such as negative impact on patients' quality of life. Thus, various strategies have been established to produce drugs capable of increasing of bone density and decreasing of the risk of bone fracture.
To date, bisphosphonate (alendronate, etidronate), hormones (raloxifen), vitamin D, calcitonin, calcium agents, or the like have been used as an anti-osteoporotic agent, and Forteo™, a form of parathyroid hormone responsible for bone formation, is currently used to treat advanced osteoporosis. However, they are known to have adverse effects. Specifically, hormone agents must be administered throughout patient's life, and in the case of long-term administration, side effects such as breast cancer, uterus cancer, gallstones and thrombosis may be induced. Vitamin D agents are expensive and show little efficacy, and calcitonin agents are also very expensive and difficult to administer. Calcium agents have few side effects, but their effects are restricted to the prevention of osteoporosis, not the treatment itself. Forteo™, a commercially available parathyroid hormone, has an advantage in that it stimulates bone formation, whereas the known drugs are restricted to the prevention of bone resorption. However, Forteo™ should be given as a daily injection for a long period of time, and may increase the risk of osteosarcoma. Its application is also restricted due to the high price.
A bisphosphonate drug, alendronate, represented by the following Formula, has been widely used for the treatment of osteoporosis, and shown to increase bone density and prevent fractures as an inhibitor of bone resorption. Owing to advantages of oral administration and lower cost, it has been widely used in clinical fields for the treatment of calcium metabolic disorders including osteoporosis.

However, bisphosphonate agents show low absorptivity and may induce esophagitis, and thus should be taken with a sufficient amount of water before meals. In addition, patients should wait at least 30 minutes before ingesting other beverage or food, and avoid lying down for a predetermined time following administration. They are also reported to increase the risk of hypocalcemia. Recent studies have suggested problems such as reduction in bone turnover rate due to excessive inhibition of bone resorption, inhibition of bone formation, gastrointestinal disorders and osteonecrosis of the jaw. Furthermore, it is recently reported that its long term administration increases the risk of bone fractures (Andrew S Neviaser et al, Journal of Othopaedic Trauma, 2008, 22(5), 346-350).
As described above, the current therapeutic agents for osteoporosis are not those which act on both bone resorption and formation. Accordingly, in order to treat osteoporosis, there is a need for the development of drugs and therapies which lead to balanced increase in the bone mass and improvement of bone quality, and thus reduce the risk of bone fractures.
To overcome the above drawbacks and improve the clinical efficacy, many studies have been made, and recent studies suggested combination therapy of a bone resorption inhibitor and a commercially available parathyroid hormone that stimulates bone formation. The detailed description thereof is as follows.
The combination therapy of alendronate and other bone resorption inhibitor are exemplified by alendronate and estrogen (literature—Lindsay et al, J. Clin. Endocrinol. Metab. 84, 3073-3081 (1999)), alendronate and raloxifene (literature—Johnell et al, J. Clin. Endocrinol. Metab. 87, 985-992 (2002)), alendronate and HRT (hormone replacement therapy) (literature—Greenspan et al, JAMA, 289, 2525-2533 (2003)), and alendronate and calcitriol (WO 01/28564). These studies demonstrated that the combination therapy showed an increase in bone density, compared to their individual administration, but no reduction in the risk of bone fracture. Moreover, problems including reduction in bone turnover rate due to inhibitory effect on bone resorption and inhibition of bone formation still remain, even though there are differences between their mechanisms. Thus, there are needs for considerations and further studies regarding the therapies.
In this regard, there was a trial of combination therapy with a bone formation stimulator, which was intended to reduce inhibitory effect on bone formation and adverse effects of alendronate. Combination therapy of alendronate with a parathyroid hormone is exemplified by two literatures: The effects of parathyroid hormone and alendronate in combination in postmenopausal osteoporosis (literature—Black et al, N. Eng. J. Med. 349, 1207-1215, (2003)) and in elderly men with osteoporosis (literature—Finkelstein et al, N. Eng. J. Med. 349, 1216-1226, (2003)). However, the literatures did not demonstrate the increase in bone density, compared to their individual administration. In this regard, some researchers suggested the possibility that a strong bone resorption inhibitor, alendronate counteracts the stimulating effect of parathyroid hormone. Subsequently, a sequential administration of two drugs has been tried, but further studies are still needed for a meaningful clinical outcome.
On the other hand, the present inventors have confirmed that the benzamidine derivative, N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine and 4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine or salts thereof are very useful as a prophylactic and therapeutic agent for osteoporosis, which is disclosed in Korea Patent No. 454767.

Accordingly, the present inventors have studied that the ingredients of Formulae 1 and 2 being useful for the prevention and treatment of osteoporosis are administered in combination with conventional bone resorption inhibitors, such as bisphosphonate (alendronate), hormones (raloxifen), vitamin D, calcitonin and calcium agents, and bone formation stimulators, and developed a new therapy to offer their benefits without their potential drawbacks.
Consequently, the present inventors have confirmed that N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine, 4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine or salts thereof and alendronic acid or a salt thereof capable of being used as a single formulation are administered in combination to provide an excellent pharmaceutical composition for preventing or treating osteoporosis, thereby completing the present invention.